1. Field of the Invention
This invention concerns a new polymeric compound which when ingested by a mammal undergoes reaction with gastrointestinal bacteria to release a pharmacologically active agent.
2. The Prior Art
Salicylazosulfapyridine (SASP) ##STR1## has been shown to be the most effective of the various sulfonamides in the treatment of ulcerative colitis and has been used clinically for over 30 years.
Upon oral ingestion, roughly 30% of the intact drug is directly absorbed from the upper small intestine. The remainder (.about.70%) suffers reductive azo cleavage in the caecum to give sulfapyridine (SP) and 5-aminosalicyclic acid (5-ASA). ##STR2## Absorbed SASP undergoes enterohepatic circulation and eventually is cleaved in the colon. Two to ten percent is excreted intact in urine. Sulfapyridine is absorbed, distributed throughout the body, and excreted in urine as glucuronide conjugates. Approximately 30% of the 5-ASA is absorbed from the colon; the remainder is excreted in the feces.
A limitation to the use of SASP is development of adverse side effects, which can be gastrointestinal (nausea, vomiting, anorexia, abdominal discomfort), hematologic (hemolytic anemia, leukopenia, transient reticulocytosis, pacytopenia), or generalized (headaches, vertigo, rashes, fever, cyanosis). In addition to these relatively common side effects, more serious adverse reactions have also been reported in the medical literature. These include agranulocytosis, toxic epidermal necrolysis, paresthesia, pancreatitis and pulmonary disease.
The toxic symptoms ascribed to SASP have been correlated with high serum concentrations of SP (&gt;50 .mu.g/ml) and decreased ability to acetylate SP. No correlation was observed with serum concentrations of SASP, SP metabolite, or 5-ASA.
The therapeutic mechanism of SASP could, in theory, be related to the intact drug or to either the antibacterial (SP) or antiinflammatory (5-ASA) cleavage product. In a recent study reported by P. Sharon et al., Gastroenterology, 75, 638-40 (1978), patients with ulcerative colitis were administered enemas of SASP and the two azo-cleavage products. About 75% of those who received SASP or 5-ASA improved, while only 38% of those who received SP showed a similar change. This significant difference, supported by sigmoidoscopy and biopsy findings, strongly suggests that 5-ASA is the therapeutic agent.
Assuming this hypothesis correct, we have reasoned that the toxic sulfapyridine portion of SASP merely serves to minimize intestinal absorption until 5-ASA can be generated by colonic bacterial reduction. A polymer leashed form of 5-ASA would be expected to be more effective than SASP for the site-specific release of 5-ASA in the colon. The potentional advantages of the polymeric drug include nonabsorption in the small intestine (i.e., controlled release) and elimination of side effects caused by SP.